Aggregates of spherical multivalent metal alginate microparticles and methods of making them

ABSTRACT

The present inventors have made studies for the purpose of establishing a process for preparing controlled-release preparations which can rapidly release 99% or more of a slightly soluble medicament (which has by itself shows a slow dissolution rate) in the upper part of the small intestine. As a result, the inventors have succeeded in establishing a process comprising carrying a slightly soluble medicament which has a slow intestinal dissolution rate on aggregates of the spherical microparticles of a multivalent metal alginate, in which each of the secondary particles (i.e., the aggregates) has a specific surface area ranging from 1 to 280 m 2 /g. This success leads to the accomplishment of the present invention.

RELATED APPLICATIONS

This application claims the benefit of priority under 35 U.S.C. §371 toPatent Convention Treaty (PCT) International Application Ser. No:PCT/JP98/04910, filed on Oct. 29, 1998, which claims benefit of priorityto JP 314591/1997, filed Oct. 31, 1997. The aforementioned applicationsare explicitly incorporated herein by reference in their entirety andfor all purposes.

TECHNICAL FIELD

The present invention relates to a process for processing alginic acid,which has conventionally been used as a thickening agent, a gelatinizingagent and a stabilizing agent in the fields of foods, pharmaceuticalsand cosmetics, into a water-insoluble spherical microparticle aggregateapplicable to other new fields including chemical industries andagriculture as well as the above-mentioned conventional fields; and anaggregate of multivalent metal alginate microparticles produced by theprocess. In particular, the present invention relates to an aggregate ofmultivalent metal alginate microparticles which is suitable as a carrierof a controlled-release preparation and a process for producing theaggregate. More specifically, the present invention relates to acontrolled-release preparation which comprises aggregates of multivalentmetal alginate microparticles as a carrier and a slightly solublemedicament having a slow dissolution rate carried on the aggregates andwhich can release the medicament rapidly in the upper part of the smallintestine, and a process for producing the controlled-releasepreparation.

BACKGROUND ART

In the conventional pharmaceutical preparations for oral administrationwhich contains a slightly soluble medicament, the medicament shows asmall dissolution rate in the digestive tract. Therefore, the amount ofthe dissolved medicament per a certain time of period is small, theabsorption of the medicament through the digestive tract is delayed, andthe amount of the medicament absorbed through the digestive tract perhour becomes small, resulting in slow absorption in a living body and alow bioavailability. In these situations, improvement in solubility ofthe slightly soluble medicament has been desired for effectivemanifestation of the efficacy and the quick-acting nature of themedicament.

As examples of the methods previously proposed for improving thesolubility of a slightly soluble medicament, Japanese Patent No. 2516524discloses a method for reducing the particle size of and amorphizing aslightly soluble, crystalline medicament (e.g., nifedipine,indomethacin); and Japanese Patent Application Laid-open Publication No.54-2316 discloses a method for preparing powders or granules from soliddispersions comprising nifedipine and polyvinylpyrrolidone, whichcomprises dissolving nifedipine and polyvinylpyrrolidone in an organicsolvent (e.g., methanol) to give a solution and then removing theorganic solvent therefrom.

Among the commercially available nifedipine preparations, a preparationin which poly(ethylene glycol) is used to form a solid dispersion ofnifedipine is “Adalat” (Bayer); and a preparation in which nifedipine isdissolved in an organic solvent and coated on lactose is “Sepamit”(Kanebo, Ltd.).

As a example of amorphization, Japanese Patent Publication No. 54-29565discloses a method comprising adding a plurality of medicamentsincluding a slightly soluble base medicament into a β-1,4-glucane andco-ground the medicaments. In this method, the β-1,4-glucane used is amicrocrystalline cellulose “Avicel” (a trade name, Asahi ChemicalIndustry Co., Ltd.); examples of the slightly soluble base medicamentare phenacetin, phenoxymethyl penicillin and phenobarbital; examples ofthe other medicaments simultaneously used with the base medicament areslightly soluble cortisone acetate, soluble tetracycline hydrochlorideand water-soluble pyridoxine hydrochloride; the grinding apparatus forco-grinding of the medicaments is one having mechanisms for mechanicallycrushing and grinding the medicaments into a microcrystalline form, suchas a ball mill; and the co-grinding is continued until the crystallinesubstances cause no diffraction peak specific to the crystallinesubstances, that is, from several hours to 10-odd hours which isrequired for complete amorphization.

Methods for preparing a solid dispersion of nifedipine with an organicsolvent are disclosed in Japanese Patent Application Laid-open No.54-2316 (supra) and Japanese Patent Publication No. 3-7645.

A method for improving the dissolution rate of a slightly solublemedicament is disclosed in Japanese Patent Publication No. 5-66364 inwhich a slightly soluble medicament and a water-soluble polymer are fedto a twin-roll mill (which is equipped with horizontal two rolls whichrotate in opposing directions to each other) through a gap between therolls while rotating the rolls, and kneaded by the rotation of therolls.

A method for preparing an easy-absorbable nifedipine preparation whichis stable to moisture is disclosed in Japanese Patent Publication No.3-28404, by which it becomes possible to improve the dissolutionproperties, particular dissolution rate, of nifedipine in water and,thereby, to produce a preparation stable to moisture compared to theconventional solid solution powdery preparations containingpolyvinylpyrrolidone.

This method comprises the steps of granulating a pharmaceutical additive(e.g., lactose) and a water-soluble binder (e.g., polyvinylpyrrolidone)to give a water-soluble fine particulate carrier, spraying a solution ofnifedipine and either hydroxypropylmethylcellulose or methylcellulose ina solvent (e.g., ethanol) on the carrier, and then drying the sprayedcarrier. The nifedipine preparation provided by this method is one inwhich nifedipine is coated in the form of a solid dispersion. Thepreparation thus produced is easy-to-dissolve or easy-to-absorb and isstable to moisture.

A medicament complex comprising a base medicament hardly soluble towater (e.g., phenacetin) which is carried on the surface of a modifiedstarch (e.g., pregelatinized starch), is disclosed in Japanese PatentPublication No. 7-47548. In this patent publication, it is describedthat the dissolution rate of the base medicament of the medicinalcomplex is increased as determined by the dissolution test (the secondsolution, pH 6.8) of the base medicament performed in accordance withthe paddle method described in the Japanese Pharmacopoeia Tenth Edition,and thereby the solubility of the base medicament is improved.

A method for improving the dissolution properties of a crystallinemedicament that is intestinally slightly soluble to the intestinal juiceis disclosed in Japanese Patent Application Laid-open No. 6-227969. Thismethod comprises the steps of dissolving an enteric polymer (e.g.,calboxymethylethylcellulose; a product of FREUND INDUSTRIAL CO., LTD.)with a mixed solvent of methylene chloride and ethanol to give asolution, dispersing indomethacin particles (mean particle diameter: 10μm) or mefenamic acid particles (mean particle diameter: 27 μm) in airas the crystalline medicament particles slightly soluble to theintestinal juice, spraying the above-prepared solution to the particlesto adhere the enteric polymer on the particles, and drying theparticles.

A method for improving the dissolution properties of a crystallinemedicament slightly soluble to water is disclosed in Japanese PatentApplication Laid-open No. 7-112928. This method comprises the steps ofdissolving nifedipine (mean particle diameter: 20 μm) into ethanol togive a solution, spraying the solution to a hydrophilic substance (e.g.,lactose; mean particle diameter: 5-10 μm) to make carry the medicament(i.e., nifedipine) on the hydrophilic substance, granulating themedicament-carried hydrophilic substance together with a water-solublepolymer (e.g., hydroxypropyl cellulose) as a binder.

Alginate gel beads are disclosed in Japanese Patent ApplicationLaid-open No. 2-167220, where a sustained-release preparation isdescribed in which a basic medicament (e.g., nifedipine) is included inthe alginate gel beads. In this patent application, thesustained-release preparation is produced by adding a suspension of thebasic medicament in a sodium alginate solution to a calcium chloridesolution dropwise through a nozzle, keeping the solution to stand,thereby forming alginate gel beads as the sustained-release preparation.In this case, the obtained alginate gel beads are assumed to beconverted to calcium alginate gel beads.

Japanese Patent Application Laid-open No. 5-39228 discloses calciumalginate beads containing nifedipine, which is prepared by adding analginic acid propylene glycol ester and/or sodium alginate to water togive a solution, adding the solution to a calcium chloride solutiondropwise through a nozzle, stirring the solution, keeping the resultantsolution to stand for 72 hours, washing the solution with water, dryingthe solution in air, and then further drying the resultant in vacuo atroom temperature. The beads thus prepared act as a sustained-releasepreparation, and is assumed to take a gel form.

Japanese Patent Application Laid-open No. 5-222208 discloses perfectlyspherical calcium alginate beads in which alginic acid ision-crosslinked via bivalent metal ions such as calcium ions and whichhave a particle size ranging from 0.1 to 30 μm.

Japanese Patent Application Laid-open No. 6-100468 discloses asustained-release composition comprising a content to be released (e.g.,phenytoin, diclofenac sodium, brilliant blue), alginic acid andhyaluronic acid. In this patent application, a typical sustained-releasepreparation is prepared by adding an aqueous solution containingdiclofenac sodium, sodium alginate and hyaluronic acid to a calciumchloride solution dropwise through a nozzle, keeping the solution tostand at room temperature for 24 hours, and washing the solution withdistilled water. In this method, it is thought that the sodium alginateused is converted into gelatinous calcium alginate.

Japanese Patent No. 2516524 discloses a method in which nifedipine orindomethacin and crosslinked polyvinylpyrrolidone are ground whilemixing continuously for 48 hours with a ball mill to amorphize thenifedipine or indomethacin. This method has such a disadvantage that itrequires too much time to grind. Japanese Patent Publication No.54-29565 discloses a method in which microcrystalline cellulose and amedicament are co-ground until any diffraction peak caused by thecrystal structure disappear. This method also has a disadvantage that itrequires too much time to co-grind. Therefore, both the methods have aproblem in production efficiency.

The method disclosed in Japanese Patent Application Laid-open No.54-2316 is a wet system with an organic solvent. In the compositionproduced by this process, nifedipine is present in the state wherenifedipine is dissolved in a matrix (e.g., polyvinylpyrrolidone) to forma glassy or solid solution-like structure. Accordingly, the compositionis not well satisfactory from the veiwpoint of rapid dissolution ofnifedipine in the intestine.

The method disclosed in Japanese Patent Publication No. 5-66364 has ashorter manufacturing period. However, this method requires a heatingprocess. In the method disclosed in Japanese Patent Publication No.3-28404, the production process is complicated. Accordingly, both ofthese methods have a problem of increased production cost. In JapanesePatent Publication No. 7-47548, partially pregelatinized starch isexemplified as a preferable carrier. However, the preparation of thispatent publication is not also satisfactory as a controlled-releasepreparation for releasing the medicament in the intestine, because itcarries the medicament only on the surface of the starch.

Each of Japanese Patent Application Laid-open Nos. 2-167220, 5-39228,6-100468 and 6-25013 discloses a controlled-release preparation in whicha medicament is included in calcium alginate gel beads.

Japanese Patent Application Laid-open Nos. 6-227969 and 7-112928disclose processes performed in air. The processes are not suitable formass production.

Accordingly, the object of the present invention is to provide acontrolled-release preparation capable of rapidly releasing a slightlysoluble medicament that has a slow intestinal dissolution rate in theintestine and a process for preparing the controlled-releasepreparation. Another object of the present invention is to provide acontrolled-release preparation capable of releasing in the intestine 99%or more of the slightly soluble medicament from the carrier and aprocess for preparing the controlled-release preparation.

DISCLOSURE OF THE INVENTION

The present inventors have studies for the purpose of establishing aprocess for preparing a controlled-release preparation capable ofreleasing in the upper part of the small intestine 99% or more of aslightly soluble medicament that has a slow intestinal dissolution rateby itself. As a result, the inventors have succeeded in establishing aprocess for making carry a slightly soluble medicament that has a slowintestinal dissolution rate by itself on aggregates of sphericalmicroparticles of multivalent metal alginate in which each of thesecondary particles has a specific surface area ranging from 1 to 280m²/g. This success leads to the accomplishment of the present invention.

That is, the present invention encompasses the invention comprised ofthe following technical subjects.

(1) An aggregate of spherical microparticles of a multivalent metalalginate, comprising a secondary particle which is an aggregate ofprimary particles of the multivalent metal alginate, wherein the meanparticle diameter of the primary particles is within the range from 0.01to 5 μm inclusive, and the specific surface area of the secondaryparticle is within the range from 1 to 280 m²/g inclusive.

(2) The aggregate of item (1), wherein the multivalent metal alginate iscalcium alginate.

(3) The aggregate of item (1) or (2), wherein the primary particles havea mean particle diameter ranging from 0.01 to 5 μm inclusive, preferablyfrom 0.05 to 1 μm inclusive, and each of the secondary particle has aspecific surface area ranging from 1 to 5 m²/g inclusive.

(4) A process for preparing aggregates of spherical microparticles of amultivalent metal alginate, which comprises the steps of:

adding an aqueous sodium alginate solution and/or an aqueous alginicacid solution to a non-aqueous solvent mainly comprising a polyhydricalcohol fatty acid ester, and then adding an emulsifying agent to theformed mixture so as to cause emulsion-dispersion, thereby forming awater-in-oil (W/O) type emulsion;

adding an aqueous solution of a multivalent metal salt to the emulsionto form spherical microparticles of the multivalent metal alginate; and

spray-drying a suspension of the spherical microparticles in water,thereby forming aggregates of the spherical microparticles.

(5) The process of item (4), wherein the aggregate is a secondaryparticle which is an aggregate of the primary particles of the sphericalmicroparticles having a mean particle diameter ranging from 0.01 to 5 μminclusive, and wherein the aggregate has a specific surface area rangingfrom 1 to 280 m²/g inclusive.

(6) The process of item (4) or (5), wherein the polyhydric alcohol fattyacid ester is at least one compound selected from the group consistingof glycerol fatty acid esters and propylene glycol fatty acid esters,the constituent fatty acid of the ester having 18 or less carbon atomsand a melting temperature of 50° C. or less.

(7) The process of any one of items (4) to (6), wherein the emulsifyingagent is at least one compound selected from the group consisting ofsorbitan fatty acid esters, polyglycerol fatty acid esters andpolylycinoleic acid polyglycerol esters.

(8) The process of any one of claims (4) to (7), wherein the multivalentmetal is at least one metal having a valency of 2 or more selected fromthe group consisting of calcium, zinc, beryllium, copper, barium,cadmium, strontium, radium, iron, aluminum, cobalt, nickel, chromium andmanganese.

(9) The process of any one of claims (4) to (8), wherein the multivalentmetal is calcium.

(10) A controlled-release preparation comprising aggregates of sphericalmicroparticles of a multivalent metal alginate, together with a slightlysoluble medicament carried on the aggregates, wherein the aggregate is asecondary particle which is an aggregate of the primary particles of themultivalent metal alginate, the mean particle diameter of the primaryparticles is within the range from 0.01 to 5 μm inclusive, and thespecific surface area of the secondary particle is within the range from1 to 280 m²/g inclusive.

(11) The controlled-release preparation of item (10), wherein theslightly soluble medicament is at least one compound selected from thegroup consisting of acetaminophen, aspirin, indomethacin, ethenzamide,ibuprofen and diclofenac sodium.

(12) The controlled-release preparation of item (10) or (11), whereinthe multivalent metal alginate is calcium alginate, and the slightlysoluble medicament is carried on the aggregates of the sphericalmicroparticles of calcium alginate.

(13) The controlled-release preparation of any one of items (10) to(12), which comprises 1 part by weight of the aggregates of thespherical microparticles of the calcium alginate and 0.01 to 10 parts byweight of the slightly soluble medicament.

(14) The controlled-release preparation of any one of items (10) to(13), wherein the dissolution rate of the slightly soluble medicament inthe artificial intestinal juice (the second solution, pH 6.8) is 99% ormore within 30 minutes.

(15) The controlled-release preparation of any one of items (10) to(14), wherein the dissolution rate of the slightly soluble medicament inthe artificial intestinal juice (the second solution, pH 6.8) is 95% ormore within 15 minutes.

(16) A process for preparing a controlled-release preparation of any oneof items (10) to (15), which comprises mixing the aggregates of thespherical microparticles of the multivalent metal alginate with theslightly soluble medicament in a dry system.

(17) A process for preparing a controlled-release preparation of any oneof items (10) to (16), which comprises mixing the aggregates of thespherical microparticles of the multivalent metal alginate with theslightly soluble medicament in a wet system.

(18) The process of item (16) or (17), wherein the aggregate of thespherical microparticles of the multivalent metal alginate is of calciumalginate.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a photograph showing the surface of CAB observed under ascanning electron microscope (magnification: 5000 times)

FIG. 2 is a photograph showing the surface of AAP-carried CAB observedunder a scanning electron microscope (magnification: 5000 times).

FIG. 3 is a graphical illustration showing the dissolution rates of aslightly soluble medicament carried on various carriers.

FIG. 4 is a graphical illustration showing the dissolution rates of aslightly soluble medicament carried on various carriers.

BEST MODE FOR CARRYING OUT THE INVENTION

The microparticles of the multivalent metal alginate used as the primaryparticles in the aggregates of the present invention are microparticlesof an alginate of a metal having a valency of two or more selected fromthe group consisting of calcium, zinc, beryllium, copper, barium,cadmium, strontium, radium, iron, aluminum, cobalt, nickel, chromium andmanganese, which have a mean particle diameter ranging from 0.01 to 5μm, preferably ranging from 0.05 to 1.0 μm.

The primary particles comprising the multivalent metal alginatemicroparticles can be prepared by the steps of mixing an aqueoussolution of a seaweed-derived alginic acid with a polyhydric alcoholfatty acid ester selected from the group consisting of a glycerol fattyacid ester and a propylene glycol fatty acid ester to form awater-in-oil (W/O) type emulsion; mechanically dispersing the W/O typeemulsion into a non-aqueous solvent containing at least one emulsifyingagent selected from the group consisting of a sorbitan fatty acid ester,a polyglycerol fatty acid ester and a poly(lecinoleic acid) polyglycerolester to make the W/O type emulsion stable, thereby forming a stable W/Otype emulsion; and emulsion-mixing the stable W/O type emulsion with anaqueous solution of at least one metal salt which is capable of forminga water-insoluble product when reacted with an alginic acid, where themetal is a bivalent metal selected from the group consisting of calcium,zinc, beryllium, copper, barium, cadmium, strontium and radium or ametal having a valency of three or more selected from the groupconsisting of iron, aluminum, cobalt, nickel, chromium and manganese.

The seaweed-derived alginic acid used for preparation of the primaryparticles is a long-chain copolymer (molecular weight: 4,000-180,000) ofD-mannuronic acid and L-glucuronic acid, and is used in the form of0.1-5 wt %, preferably 0.5-2 wt % of an aqueous solution. The alginicacid may also be used in the form of an alkali metal salt which exhibitsa good solubility, such as sodium alginate.

The polyhydric alcohol fatty acid ester, which constitutes an oil-basedcontinuous layer of the emulsion, is preferably those having a dynamicinterfacial tension against water as low as possible, so that theparticle diameters of the W/o emulsion particles can be adjusted tothose of sub-micron orders. Preferably, in the polyhydric alcohol fattyacid ester, the constituent fatty acid has 18 or less of carbon atomsand a melting temperature of 50° C. or less. Preferable example of thepolyhydric alcohol fatty acid ester include fatty acid glycerides suchas oleic acid mono- or di-glycerides and linoleic acid mono- ordi-glycerides; organic acid monoglycerides each comprising any of thesemono-glycerides into which an organic acid (e.g., citric acid, succinicacid, malic acid, diacetyltartaric acid) is introduced; andtriglycerides of middle-chain (C6-C12) fatty acids. Besides, propyleneglycol fatty acid esters are also preferable, including caprylic acidmono- or di-esters, capronic acid mono- or di-esters, and organic esterseach comprising any of these esters into which an organic acid (e.g.,citric acid, succinic acid, malic acid, diacetyltartaric acid) isintroduced.

These polyhydric alcohol fatty acid esters are safe and have superior inprocessability because they show no volatility or inflammability atordinary temperatures.

The sorbitan fatty acid ester used as an emulsifying agent preferablyhas an esterification degree ranging from about 20% to about 75%. Theconstituent fatty acid of the sorbitan fatty acid ester is preferably anunsaturated fatty acid, such as oleic acid, linolic acid, linolenicacid, or a mixture thereof.

The polyglycerol fatty acid ester preferably has an esterificationdegree ranging from about 20% to about 75% and a condensation degree ofthe polyglycerol ranging from 2 to 10. Especially preferable example ofthe polyglycerol fatty acid ester include diglycerol monooleate,triglucerol dioleate, tetraglycerol trioleate, pentaglyceroltetraoleate, hexaglycerol tetraoleate, hexaglycerol pentaoleate,decaglycerol pentaoleate and decaglycerol heptaoleate.

The poly(ricinoleic acid) polyglycerol fatty acid ester preferably has acondensation degree of the ricinoleic acid ranging from 2 to 6 and acondensation degree of the polyglycerol ranging from 4 to 10.

The multivalent metal salt which is cable of forming a water-insolubleproduct when reacted with the alginic acid can be prepared as a 1-20 wt% aqueous solution or a 1-20 wt % water-containing alcohol solution. Themultivalent metal salt may be any one selected from the salts of themetals each having a valency of 2 or more, such as calcium, zinc,beryllium, copper, barium, cadmium, strontium, radium, iron, aluminum,cobalt, nickel, chromium and manganese, or may be used as a mixture oftwo or more of these metals. The multivalent metal salt is contactedwith the W/O micelle of the alginic acid in the form of a W/O micelle tocause cross-bonding between the two carboxyl groups in the alginic acid,thereby forming water-insoluble spherical microparticles of the metalalginate.

After the formed spherical microparticles of the metal alginate aretreated to make them insoluble, the spherical microparticles areexcluded out of the W/O emulsion system by further adding the sameaqueous multivalent metal salt solution as used just before thisprocedure to the emulsion system in an amount three times or larger.Thus the spherical microparticles can be collected from the oil-basedcontinuous layer easily with a centrifuge capable of providing anacceleration of gravity of 1500×g or more. The collected sphericalalginate microparticles are washed with hot water to remove theundesired substances remaining on the surfaces and the insides of themicroparticles, such as the emulsifying agent, the multivalent metalsalts and the low molecular alginic acid components which are not usedfor the cross-linkage.

The primary particle, which is the spherical microparticle of amultivalent metal alginate of the present invention, is characterized byhaving mean particle diameter ranging from 0.01 to 5 μm. Theabove-mentioned secondary particle, which is an aggregate of the primaryparticle, may be suitable as carriers for a controlled-releasepreparation. The primary particles may also be used as an additive for acoating film having a thickness of sub-micron order or for a syntheticfiber. Therefore, the primary particles may also be applicable as usefulspherical microparticles in the fields that attach importance tofeelings, such as the filed of skin cosmetics where it is required forthe diameters of the particles to be 10 μm or smaller which areperceptible by a human.

The primary particles of the present invention, which comprise thespherical multivalent metal alginate microparticles, are suspended intowater and then spray-dried to cause aggregation of the particles and tothereby form larger secondary particles. Thus, aggregates of thespherical metal alginate microparticles each having a specific surfacearea ranging from 1 to 280 m²/g can be produced.

The aggregate of the spherical multivalent metal alginate microparticlespreferably used in the present invention is an aggregate of sphericalcalcium alginate microparticles [hereinafter, simply referred to as“calcium alginate bead” or “CAB”]. CAB can be produced by granulatingsodium alginate extracted from a brown seaweed, such as sea tangle (thegenus Laminaria) and edible seaweed (the genus Eisenia), into nearlyperfectly spherical forms and then making the granule insoluble withcalcium ions, of which the primary particles have a mean particlediameter ranging from 0.01 to 5 μm, preferably ranging from 0.05 to 1μm, and the secondary particle has a specific surface area ranging from1 to 280 m²/g, preferably ranging from 1 to 50 m²/g, more preferablyranging from 1 to 5 m²/g, as measured by the BET method. As commerciallyavailable CAB, “Flavikafine” (a trade name; Nisshinbo Industries, Inc.)is preferably used.

In the aggregates of the spherical multivalent metal alginatemicroparticles of the present invention, if the mean particle diameterof the primary particles is smaller than 0.01 μm, the adsorbingproperties of a slightly soluble medicament to the aggregates becomespoor; whereas if the mean particle diameter of the primary particles islarger than 5am, the physical strength of the aggregates becomes weak,resulting in breakage of the aggregates during mixing with a medicament.In addition, if the specific surface area of the secondary particle isless than 1 m²/g, the physical strength of the aggregates becomes weak,resulting in breakage of the aggregates during mixing with a medicament;whereas if the specific surface area is larger than 280 m²/g, theadsorbing properties of the medicament to the aggregates becomes poor.Therefore, the mean particle diameter of the primary particles and thespecific surface area of the secondary particle not falling within theabove-mentioned ranges are not preferable.

When CAB, which is an aggregate of the spherical multivalent metalalginate microparticles preferably used in the present invention, weredetermined on the mean particle diameter distribution with a laserdiffraction/scattering-type mean particle diameter analyzer (“HEROS”;Sysmpatec) on a volume base, it was found that CAB has a mean particlediameter ranging from 5 to 50 μm when dispersed in a dry system (withouta solvent) and from 0.5 to 5 μm when dispersed in water.

When the particle diameter of CAB was determined by observation under ascanning electron microscope, it was found that the CAB was dispersed inwater almost in the form of primary particles, whereas the primaryparticles of the CAB were aggregated to form porous secondary particlesin the dry state or when dispersed in ethanol.

Furthermore, as shown in FIGS. 1 and 2, the CAB of the present inventiontakes the form of not a gel but secondary particles. Therefore, themechanism for releasing a medicament of the CAB is different fromgel-type carriers. As shown in FIG. 2, the medicament-carried CAB alsoform secondary particles, where the medicament is carried in a quitedifferent way than the glassy carriers or the solid solution-typecarriers. Moreover, the controlled-release preparation comprising theCAB and a slightly soluble medicament carried thereon of the presentinvention is also different from a preparation in which a medicament iscarried on the surface of a single-particle carrier (e.g., starch), andhas a novel structure that has not been found previously.

As shown in the scanning electron microscopic photographs given in theexamples below, the CAB takes a nearly perfectly spherical form. Ingeneral, it is preferable that powders used as a raw material of apharmaceutical preparation take the nearly perfectly spherical form (inother words, have an aspect ratio of nearly 1) so that the powdersexhibit good flowability and quantitative property. This is because itis necessary for the powders to reduce the weight variation duringtransportation or supply of the powders to a hybridizing apparatus. Asused herein, the aspect ratio refers to the ratio between the lengths ofthe long axis and the short axis of a particle, which is a measure ofsphericity degree. The long axis/short axis ratio is obtained by placingparticles randomly on a slide grass, taking a picture of the particlesto measure the length of the long axis (the longer diameter) and thelength of the short axis (the shorter diameter; determined by drawing aline perpendicular to the long axis at its midpoint) for each of 50particles, calculating the ratio of the length of the long axis to thelength of the short axis for each particle, and then averaging thecalculated values of the 50 particles. The secondary particle of the CABpreferably used in the present invention characteristically also has anaspect ratio of nearly 1, which is 1.2 or less and preferably 1.1 orless.

The controlled-release preparation according to the present inventioncan be prepared by making carry a slightly soluble medicament on theaggregates of the spherical multivalent metal alginate microparticlesproduced by the process mentioned above.

The slightly soluble medicament used in the present invention may be anysubstance that exhibits a medicinal efficacy, is pharmaceuticallyacceptable, is confirmed to the Japanese Pharmacopoeia (the 13thAmendment) and requires 30 ml or more of water to dissolve 1 g of thesubstance.

Examples of the slightly soluble medicament include acetaminophen,aspirin, indomethacin, ethenzamide and nifedipine. The solubilities ofthese substances in water are shown in Table 1, respectively. The unitof each numerical value shown in Table 1 is the weight (mg) of each ofthe slightly soluble medicaments capable of dissolving in 1 m of thesolvent (water).

As used herein, the term “solubility” in accordance with the JapanesePharmacopoeia (the 13th Amendment) refers to the degree of dissolutionof a medicament in a solvent within 30 minutes when 1 g of themedicament is added to the solvent and mixing them with vigorous shakingat intervals of 5 minutes at 20° C.±5° C. In the present specification,the solubility is evaluated in accordance with this method. When theamount (ml) of water required to dissolve 1 g of a medicament is 30 mlor more, the solubility of the medicament represents the grades of“slightly soluble” or “hardly soluble”. In accordance with the standardof the U.S. Pharmacopoeia 21 (1985), the term “slightly soluble” isdefined as “sparingly soluble”.

TABLE 1 (unit: mg/ml) Slightly soluble medicament Water Acetaminophen13.1 Aspirin 3.63 Indomethacin less than 0.1 Ethenzamide less than 0.1

In the controlled-release preparation of the present invention, amedicament selected from the group consisting of acetaminophen, aspirin,indomethacin, ethenzamide, ibuprofen and diclofenac sodium or acombination of two or more of them is carried as a slightly solublemedicament on the aggregates of spherical calcium alginatemicroparticles such as the CAB mentioned above. The controlled-releasepreparation carries 0.01 to 10 parts by weight of the slightly solublemedicament per 1 part by weight of the CAB.

The controlled-release preparation of the present invention is alsocharacterized in that a dissolution rate of the slightly solublemedicament in the artificial intestinal juice (the second solution, pH6.8) is 99% or more within 30 minutes.

The controlled-release preparation of the present invention is alsocharacterized in that a dissolution rate of the slightly solublemedicament in the artificial intestinal juice (the second solution, pH6.8) is 95% or more within 15 minutes.

The controlled-release preparation of the present invention may beformulated into tablets with an excipient, or powders or granules bygranulating the medicament-carried CAB. The tables, powders or granulesmay be coated with an enteric coating film material to provide anenteric preparation. The granules may also be encapsulated intocapsules.

The controlled-release preparation of the present invention can beprepared by hybridizing the slightly soluble medicament with theaggregates of spherical multivalent metal alginate microparticles in adry system or a wet system.

In the preparation of the controlled-release preparation of the presentinvention, the term “dry system” means a system without any solvent(e.g., water, an organic solvent), and the term “wet system” means asystem with a solvent (e.g., water, an organic solvent).

The organic solvent used in the present invention is ethanol alone or amixed solvent of, for example, water-containing ethanol or a mixedsolvent such as that of ethanol and methylene chloride. However, ingeneral, ethanol alone is preferably used.

By employing a wet system, it become possible to include the medicamentwithin the secondary particles of the aggregates of the sphericalmultivalent metal alginate microparticles. In other words, the secondaryparticles of the CAB can carry the medicament in the spaces between theprimary particles constituting the secondary particles and, thereby, actas a microsponge and exhibit porous substance-like functions.

As used herein, the term “hybridizing” or “to hybridize” means aprocedure to contact a medicament with the aggregates of the sphericalmultivalent metal alginate microparticles in order to make carry themedicament on the aggregates. In the present invention, this term meansa processing for making carry a slightly soluble medicament on theaggregates by a simple mixing, a mixing optionally accompanied bygrinding of the medicament, an emulsion dispersion, a spray drying andother processing techniques such as an air suspension coating (a processfor preparing microcapsules).

In the present invention, the mixing accompanied by grinding of themedicament can be performed with a conventional mixer or amixing-grinder. Examples of the grinder include, not limited to, a ballmill (such as a product of Kurimoto, Ltd.), a vertical jet mill (e.g., aproduct of Seishin Enterprise Co., LTD.), a planetary ball mill (e.g., aproduct of Seishin Enterprise CO., LTD.), a vibrating mill (e.g., aproduct of Chuo Kakohki CO., LTD.). As a matter of course, in thehybridizing process accompanied by grinding of the medicament, suchprocessing conditions are selected that cause no or, if any, lessdisintegration of the spherical aggregates (the secondary particles) ofthe multivalent metal alginate microparticles of the present invention.

By the hybridizing process of the present invention, the medicament canbe carried on the surfaces of the aggregates of the sphericalmultivalent metal alginate microparticles and in the spaces between themicroparticles. When put into water, the medicament-carried aggregatesthus prepared are disintegrated into the primary particles and dispersedin water.

The “drying” performed in the hybridizing process in the preparation ofthe controlled-release preparation of the present invention means todistill off the solvent (e.g., water, an organic solvent), and generallya drying procedure performed in a spray-drying apparatus is applicable.Any type of the spray-drying apparatus may be used as long as thesolvent can be distilled off by spraying a solution containing thesolvent and the aggregates of the spherical multivalent metal alginatemicroparticles in hot air, such as spray dryers produced by OhkawaraKakohki Co., Ltd. and ASHIZAWA-NIRO ATOMIZER LTD.

The temperature of the dry air in the spray-drying apparatus ispreferably not higher than 250° C. from the viewpoint of providingappropriate stability of the slightly soluble medicament and not lowerthan 100° C. from the viewpoint of drying efficacy. The spraying isperformed with an atomizer equipped with, for example, a rotary disk, atwin-flow nozzle, a nozzle or an airless nozzle.

When an atomizer equipped with a nozzle is used, the mean particlediameter distribution of the aggregates of the spherical multivalentmetal alginate microparticles with a slightly soluble medicament carriedthereon becomes sharper compared to the case where an atomizer equippedwith a rotary disk is used. Therefore, an atomizer equipped with anozzle is preferable.

Besides the above-mentioned spray-drying apparatus, any other type ofapparatus may be used as long as the destruction of the secondaryparticle structure of the aggregates of the spherical multivalent metalalginate microparticles does not occur, and a statistic drying apparatusor a fluid-bed drying apparatus may be employed appropriately.

As used herein, the term “artificial intestinal juice (the secondsolution, pH 6.8)” refers to a phosphate buffer of pH 6.8 as describedin the Japanese Pharmacopoeia (the 13th Amendment), the section ofdissolution test, the second method (paddle method). As used herein, theterm “dissolution rate” refers to a value given by dividing the actualelution concentration of a slightly soluble medicament by the calculatedelution concentration and expressing the resultant value as a percent.Here, the term “calculated elution concentration” refers to theconcentration given when hypothesizing that the entire slightly solublemedicament added to the second solution is dissolved. For example, thecalculated elution concentration of a slightly soluble medicament givenwhen 5 g of the medicament is added to 500 ml of the second solution is10 mg/ml. In this case, when the actual elution concentration is 5mg/ml, the dissolution rate is 50%.

In general, the dissolution rate of a slightly soluble medicament byitself is slow in the artificial intestinal juice, and the saturateddissolution amount is small. Therefore, the saturated dissolutionconcentration tends to be smaller than the calculated concentration. Forexample, as shown in FIG. 3, indomethacin by itself shows a dissolutionrate of less than 40% even within two hours.

The present invention will be described more in detail below by theembodiments where CAB is used as the aggregate of the sphericalmultivalent metal alginate microparticles. However, the presentinvention should not be construed to be limited by the followingexamples.

EXAMPLE 1

There were provided an aqueous sodium alginate solution (the dispersedphase; 1 liter) in which the concentration of sodium alginate wasadjusted to 5 wt % and a non-aqueous solvent (the continuous phase; 4liters) which contained poly(ricinoleic acid) polyglycerol ester inpropylene glycol dicapric acid ester in a concentration of 10 wt %.

The dispersed phase and the continuous phase were emulsified with eachother with a homomixer (10000 rpm, 10 minutes) while pouring thedispersed phase into the continuous phase to give a W/O-type emulsion.

The W/O-type emulsion was emulsion-mixed with a 20 wt % aqueous solutionof calcium chloride (1 liter) with a homomixer (10000 rpm, 10 minutes)while pouring the aqueous calcium chloride solution into the W/O-typeemulsion to cause crosslinking.

The emulsion mixture thus obtained was further mixed with a 20 wt %aqueous solution of calcium chloride (10 liters) with a homomixer (10000rpm, 10 minutes) and then subjected to centrifugation (1500×g, 10minutes) to collect spherical microparticles of calcium alginate. Thespherical microparticles thus collected were washed with hot water andthen suspended into water to give a suspension. The suspension was thenspray-dried.

It was confirmed that the spherical calcium alginate microparticlesdispersed into water had a mean particle diameter of 0.05 μm asdetermined with a laser diffraction type particle distribution analyzerand took the form of spherical particles as observed under an electronmicroscope.

EXAMPLE 2

There were provided an aqueous sodium alginate solution (the dispersedphase; 1.5 liters) in which the concentration of sodium alginate wasadjusted to 10 wt % and a non-aqueous solvent (the continuous phase; 3.5liters) which contained poly(ricinoleic acid) polyglycerol ester in amiddle-chain fatty acid triglyceride in a concentration of 5 wt %.

The dispersed phase and the continuous phase were emulsified with eachother with a homomixer (10000 rpm, 1 minutes) while pouring thedispersed phase into the continuous phase to give a W/O-type emulsion.

The W/O-type emulsion was emulsion-mixed with a 20 wt % aqueous solutionof calcium chloride (2 liters) with a homomixer (10000 rpm, 10 minutes)while pouring the aqueous calcium chloride solution into the W/O-typeemulsion to cause crosslinking.

The emulsion mixture thus obtained was further mixed with a 20 wt %aqueous solution of calcium chloride (6 liters) with a homomixer (10000rpm, 10 minutes) and then subjected to centrifugation (1500×g, 10minutes) to collect spherical microparticles of calcium alginate. Thespherical microparticles thus collected were washed with hot water andthen suspended into water to give a suspension. The suspension was thenspray-dried.

It was confirmed that the spherical calcium alginate microparticlesdispersed into water had a mean particle diameter of 1.0 μm asdetermined with a laser diffraction type particle distribution analyzerand took the form of spherical particles as observed under an electronmicroscope.

EXAMPLE 3

There were provided an aqueous sodium alginate solution (the dispersedphase; 2.5 liters) in which the concentration of sodium alginate wasadjusted to 10 wt % and a non-aqueous solvent (the continuous phase; 2.5liters) which contained sorbitan monooleic acid ester in a middle-chainfatty acid triglyceride in a concentration of 2 wt %.

The dispersed phase and the continuous phase were emulsified with eachother with a homomixer (10000 rpm, 1 minutes) while pouring thedispersed phase into the continuous phase to give a W/O-type emulsion.

The W/O-type emulsion was emulsion-mixed with a 20 wt % aqueous solutionof calcium chloride (2 liters) with a homomixer (10000 rpm, 10 minutes)while pouring the aqueous calcium chloride solution into the W/O-typeemulsion to cause crosslinking.

The emulsion mixture thus obtained was further mixed with a 20 wt %aqueous solution of calcium chloride (6 liters) with a homomixer (10000rpm, 10 minutes) and then subjected to centrifugation (1500×g, 10minutes) to collect spherical alginate microparticles. The sphericalalginate microparticles thus collected were washed with hot water andthen suspended into water to give a suspension. The suspension was thenspray-dried.

It was confirmed that the spherical alginate microparticles dispersedinto water had a mean particle diameter of 5.0 μm as determined with alaser diffraction type particle distribution analyzer and took the formof spherical particles as observed under an electron microscope.

EXAMPLE 4

The slightly soluble medicament acetaminophen (KONGO YAKUHIN CO., LTD.,hereinafter simply referred to as “AAP”; 6 g) was dissolved in ethanol(JP grade) to give a solution (50 ml). To this solution was graduallyadded the carrier calcium alginate beads (Nisshinbo Industries Inc.; atrade name “Flavikafine SF-D”, hereinafter simply referred to as “CAB”;1.0 g) and subjected to isotonification for 30 minutes. The solution wascentrifuged at 3000 rpm for 20 minutes. Subsequently the sedimented CABparticles were dried at rest at 105° C. for 4 hours to give the CAB withAAP carried thereon (hereinafter, simply referred to as “AAP-carriedCAB).

FIG. 1 shows a photograph of the CAB magnified 5000 times by a scanningelectron microscope. As is evident from the photograph, the CAB is aspherical microgranule in which the primary particles having particlediameter ranging from 0.2 to 1.0 μm are aggregated to form the secondaryparticle. The median diameter (D50) of the CAB was 14.2 μm. Thesecondary particle of the CAB has an aspect ratio of 1.1, which meansthat the CAB was a nearly true sphere.

FIG. 2 shows a photograph of the AAP-carried CAB magnified 5000 times bya scanning electron microscope. As is evident from the photograph, eachof the AAP-carried CAB particles is a spherical microgranule in whichthe primary particles having particle diameter ranging from 0.2 to 1.0μm are aggregated to form the secondary particle. The median diameter(D50) of the AAP-carried CAB was 14.3 μm. The secondary particle of theAAP-carried CAB has an aspect ratio of 1.1, which means that theAAP-carried CAB was a nearly true sphere.

The AAP content of the AAP-carried CAB was determined by the followingmanner.

That is, the AAP-carried CAB (100 mg) is dispersed into ethanol (JPgrade) (100 ml) and then subjected to isotonification for 30 minutes.The dispersion is centrifuged (3000 rpm, 20 minutes) to give an extractof AAP. The extract is subjected to determination of absorbance at anabsorption wavelength of 244 nm with a spectrophotometer.

As a result, it was found that the AAP content of the AAP-carried CABwas 16.0% (w/w).

EXAMPLE 5

The same procedure as Example 1 was repeated, except that the slightlysoluble medicament aspirin (a product of KOZAKAI SEIYAKU CO., LTD.;hereinafter, simply referred to as “AS”) was used in place of AAP togive AS-carried CAB. The photograph of the AS-carried CAB magnified 5000times by a scanning electron microscope was similar to that shown inFIG. 2. The AS content of the AS-carried CAB was 16.1% (w/w) asdetermined by the same procedure as Example 1 except that an absorptionwavelength of 278 nm was employed.

EXAMPLE 6

A slightly soluble medicament indomethacin (a product of DAIWAPHARMACEUTICAL CO., LTD,; hereinafter, simply referred to as “IMC”) (500mg) was added to the CAB and the resultant mixture was ground whilemixing with an automatic mortar (a product of Nitto Scientific CO.,LTD.) at room temperature for 1 hour.

A portion (100 mg; corresponding to 50 mg in terms of IMC) of themixing-ground product was sampled and tested in accordance with theJapanese Pharmacopoeia (the 13th Amendment), the second method of thedissolution test (i.e., the paddle method) as follows.

That is, the number of revolution of the paddle was fixed to 100 rpm,and the mixing-ground product (100 mg) was added to the second solution(a phosphate buffer; pH 6.8, 500 ml) to give a solution, and the testwas conducted at 37° C.

After addition of the mixing-ground product to the second solution, aportion of the solution was sampled once every a predetermined period oftime, and each of the sample solutions was filtered with a membranefilter (pore size: 0.2 μm). A portion (5 ml) of the filtrate wasremoved, extracted with chloroform (5 ml), and then centrifuged. Thechloroform layer given after the centrifugation was used fordetermination of the absorbance of IMC with a spectrophotometer at awavelength of 318 nm. The determination procedure was conducted twiceand the two results obtained were averaged (the variation of the resultswas small). The results are shown in FIG. 3.

The dissolution rate of the IMC-carried CAB to the first solution (pH1.2) was also determined in the same manner as above. As a result, itwas found that IMC was less released from the IMC-carried CAB and thedissolution rate within 2 hours was less than 1%.

EXAMPLE 7

Ethenzamide (a product of SHIZUOKA COFFEIN & CO, LTD.; hereinafter,simply referred to as “EZ”) was used as the slightly soluble medicamentin place of IMC. EZ (500 mg) was added to the CAB (500 mg) and theresultant mixture was ground while mixing with an automatic mortar atroom temperature for 1 hour. A portion (50 mg; corresponding to 25 mg interms of EZ) of the mixing-ground product obtained was subjected to thesame procedure as Example 3 to determine the EZ content of the product.The wavelength employed in the determination process was 290 nm. Theresults are shown in FIG. 4.

COMPARATIVE EXAMPLE 1

Crystalline cellulose (“Avicel PH-M06”, a product of Asahi ChemicalIndustry, Co., Ltd.; hereinafter, simply referred to as “CC”) was usedas a carrier. The slightly soluble medicament IMC (500 mg) was added tothe CC (500 mg) and the resultant mixture was ground while mixing withan automatic mortar at room temperature for 1 hour. A portion (100 mg;corresponding to 50 mg in terms of IMC) of the mixing-ground productobtained was subjected to the same procedure as Example 3 to determinethe IMC content of the product. The wavelength employed in thedetermination process was 318 nm. The results are shown in FIG. 3.

COMPARATIVE EXAMPLE 2

Crosslinked polyvinylpyrrolidone (“Polyplasdone XL”, a product of GAF;hereinafter, simply referred to as “CLPVP”) and polyvinylpyrrolidone(hereinafter, simply referred to as “PVP”) (500 mg each) were separatelyadded to the slightly soluble medicament IMC (500 mg), and each of theresultant mixtures was ground while mixing with an automatic mortar atroom temperature for 1 hour. A portion (100 mg; corresponding to 50 mgin terms of IMC) of each of the mixing-ground products obtained wassubjected to the same procedure as Example 3 to determine the IMCcontent of each of the products. The wavelength employed in thedetermination process was 318 nm. The results are shown in FIG. 3.

COMPARATIVE EXAMPLE 3

The same procedure as Example 6 was repeated, except that IMC alone (50mg) was used in place of the mixing-ground product (100 mg;corresponding to 50 mg in terms of IMC) to determine the IMC content ofthe product. The results are shown in Table 3.

COMPARATIVE EXAMPLE 4

Crystalline cellulose (“Avicel PH-M06”, a product of Asahi ChemicalIndustry Co., Ltd.; hereinafter, simply referred to as “CC”) (500 mg)was added to the slightly soluble medicament EZ (500 mg) and theresultant mixture was ground while mixing with an automatic mortar atroom temperature for 1 hour. A portion (50 mg; corresponding to 25 mg interms of EZ) of the mixing-ground product obtained was subjected to thesame procedure as Example 6 to determine the EZ content of the product.The wavelength employed in the determination process was 290 nm. Theresults are shown in FIG. 4.

COMPARATIVE EXAMPLE 5

Either of crosslinked polyvinylpyrrolidone (“Polyplasdone XL”, a productof GAF; hereinafter, simply referred to as “CLPVP”) orpolyvinylpyrrolidone (hereinafter, simply referred to as “PVP”) (500 mgeach) was added to the slightly soluble medicament EZ (500 mg), and theresultant mixture was ground while mixing with an automatic mortar atroom temperature for 1 hour. A portion (50 mg; corresponding to 25 mg interms of EZ) of each of the mixing-ground products obtained wassubjected to the same procedure as Example 6 to determine the EZ contentof each of the products. The wavelength employed in the determinationprocess was 290 nm. The results are shown in FIG. 4.

COMPARATIVE EXAMPLE 6

The same procedure as Example 6 was repeated, except that EZ alone (25mg) was used in place of the mixing-ground product (50 mg; correspondingto 25 mg in terms of EZ) to determine the EZ content of the product. Theresults are shown in Table 4.

INDUSTRIAL APPLICABILITY

The controlled-release preparation of the present invention in which aslightly soluble medicament is carried on the secondary particles eachcomprising an aggregate of spherical multivalent metal alginatemicroparticles is a new slightly soluble medicament-carried preparationwhich has not been known previously, and the manner to carry themedicament of the preparation is also new.

As is evident from Examples and Comparative Examples described above,the aggregates of the spherical calcium alginate microparticles of thepresent invention can remarkably improve the dissolution properties ofthe slightly soluble medicament and, therefore, can provide acontrolled-release preparation excellent in bioavailability.

Since the aggregates of the calcium alginate microparticles have aneffect to rapidly release the slightly soluble medicament carriedthereon in the second solution, it is expected that the aggregatesprovides a rapid action of the medicament.

The spherical microparticle aggregate, which is a secondary particle ofcalcium alginate microparticles, can rapidly release a slightly solublemedicament carried thereon in the second solution at an dissolution rateof 99% or more. Therefore, the aggregate is less wasteful of themedicament and highly safe upon designing pharmaceuticals that shouldmaintain the medicament in an effective blood level when administered toa subject.

After the medicament is released out of the calcium alginatemicroparticles in the second solution completely, the calcium alginateis converted into sodium alginate by the ion exchange between thecalcium ions of the calcium alginate and the sodium ions of an aqueoussodium chloride solution and the like, and changes its nature towater-soluble and finally absorbed to or eliminated from a body. Fromthis reason, the secondary particle which comprises a sphericalaggregate of calcium alginate microparticles is suitable as a carrierfor a medicament.

The calcium alginate beads with a slightly soluble medicament carriedthereon have such a desirable property that the medicament is releasedin the stomach in a small amount, released sustainedly in the upper partof the small intestine and released in the intestine in a large amount.Accordingly, it also becomes possible to formulate enteric preparationswhich can release a slightly soluble medicament not in the stomach butin the intestine by the process comprising granulating calcium alginatebeads with the medicament carried thereon, formulating themedicament-carried calcium alginate beads into the form of granules,tablets, capsules and the like, and then coating the formulations withan enteric coating such as CMC (carboxymethyl cellulose).

Accordingly, it becomes possible to impart such an unprecedentedproperty that the medicament is completely released in the intestine tothe controlled-release preparations with a medicament such asindomethacin and ethenzamide.

The controlled-release preparation of the present invention can beproduced in a short time in a dry system. Therefore, the preparation isdesirable in the viewpoint of countermeasures for the reduction ofmanufacturing costs upon formulation, and also desirable in theviewpoint of anti-GMP measure since the reduction in the numbers ofitems of process validation can be attained.

What is claimed is:
 1. A process for preparing aggregates of sphericalmicroparticles of a multivalent metal alginate, which comprises thesteps of: adding an aqueous sodium alginate solution and/or an aqueousalginic acid solution to a non-aqueous solvent comprising a polyhydricalcohol fatty acid ester, and then adding an emulsifying agent to theformed mixture so as to cause emulsion dispersion, thereby forming awater-in-oil (W/O) type emulsion; adding an aqueous solution of amultivalent metal salt to the emulsion to form spherical microparticlesof the multivalent metal alginate; and spray-drying a suspension of thespherical microparticles in water, thereby forming aggregates of thespherical microparticles.
 2. The process of claim 1, wherein theaggregate is a secondary particle which is an aggregate of a pluralityof primary spherical microparticles having a mean particle diameterranging from 0.01 to 5 μm inclusive, and wherein the aggregate has aspecific surface area ranging from 1 to 280 m²/g inclusive.
 3. Theprocess of claim 1 or 2, wherein the polyhydric alcohol fatty acid esteris at least one compound selected from the group consisting of glycerolfatty acid esters and propylene glycol fatty acid, the constituent fattyacid of the ester having 18 or less carbon atoms and a meltingtemperature of 50° C. or less.
 4. The process of claim 1 or 2, whereinthe emulsifying agent is at least one compound selected from the groupconsisting of sorbitan fatty acid esters, polyglycerol fatty acid estersand poly(rycinoleic acid) polyglycerol esters.
 5. The process of claim 1or 2, wherein the multivalent metal is at least one metal having avalency of 2 or more selected from the group consisting of calcium,zinc, beryllium, copper, barium, cadmium, strontium, radium, iron,aluminum, cobalt, nickel, chromium and manganese.
 6. The process ofclaim 1 or 2, wherein the multivalent metal is calcium.
 7. The processof claim 1, wherein the polyhydric alcohol fatty acid ester comprises afatty acid constituent of 18 or less of carbon atoms and a meltingtemperature of 50° C. or less.
 8. The process of claim 1, wherein thepolyhydric alcohol fatty acid ester comprises a fatty acid glyceride. 9.The process of claim 1, wherein the fatty acid glycerides comprises anoleic acid mono- or di- glyceride or a linoleic acid mono ordi-glyceride.
 10. The process of claim 1, wherein the polyhydric alcoholfatty acid ester comprises an organic acid monoglyceride.
 11. Theprocess of claim 10, wherein the organic acid monoglyceride comprises acitric acid, a succinic acid, a malic acid or a diacetyltartaric acid.12. The process of claim 1, wherein the polyhydric alcohol fatty acidester comprises a triglyceride of middle-chain fatty acid.
 13. Theprocess of claim 1, wherein the polyhydric alcohol fatty acid estercomprises a propylene glycol fatty acid ester.
 14. The process of claim13, wherein the propylene glycol fatty acid ester comprises a caprylicacid mono- or di-ester, a capronic acid mono- or di-ester.